Alendronate Sodium And Cholecalciferol

1 INDICATIONS AND USAGE FOSAMAX PLUS D is a combination of a bisphosphonate and vitamin D indicated for: Treatment of osteoporosis in postmenopausal women ( 1.1 ) Treatment to increase bone mass in men with osteoporosis ( 1.2 ) Limitations of use : FOSAMAX PLUS D alone should not be used to treat vitamin D deficiency. ( 1.3 ) Optimal duration of use has not been determined. For patients at low-risk for fracture, consider drug discontinuation after 3 to 5 years of use. ( 1.3 ) 1.1 Treatment of Osteoporosis in Postmenopausal Women FOSAMAX ® PLUS D is indicated for the treatment of osteoporosis in postmenopausal women. In postmenopausal women, FOSAMAX PLUS D increases bone mass and reduces the incidence of fractures, including those of the hip and spine (vertebral compression fractures). [See Clinical Studies (14.1) .] 1.2 Treatment to Increase Bone Mass in Men with Osteoporosis FOSAMAX PLUS D is indicated for treatment to increase bone mass in men with osteoporosis [see Clinical Studies (14.2) ] . 1.3 Important Limitations of Use FOSAMAX PLUS D alone should not be used to treat vitamin D deficiency. The optimal duration of use has not been determined. The safety and effectiveness of FOSAMAX PLUS D for the treatment of osteoporosis are based on clinical data of four years duration. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis. Patients at low-risk for fracture should be considered for drug discontinuation after 3 to 5 years of use. Patients who discontinue therapy should have their risk for fracture re-evaluated periodically.

2 DOSAGE AND ADMINISTRATION 70 mg alendronate/2800 international units vitamin D 3 or 70 mg alendronate/5600 international units vitamin D 3 tablet once weekly. ( 2.1 , 2.2 ) Instruct patients to: ( 2.3 ) Swallow tablets whole with 6-8 ounces plain water at least 30 minutes before the first food, drink, or medication of the day. Not lie down for at least 30 minutes after taking FOSAMAX PLUS D and until after food. 2.1 Treatment of Osteoporosis in Postmenopausal Women The recommended dosage is one 70 mg alendronate/2800 international units vitamin D 3 or one 70 mg alendronate/5600 international units vitamin D 3 tablet once weekly. For most osteoporotic women, the appropriate dose is FOSAMAX PLUS D (70 mg alendronate/5600 international units vitamin D 3 ) once weekly. 2.2 Treatment to Increase Bone Mass in Men with Osteoporosis The recommended dosage is one 70 mg alendronate/2800 international units vitamin D 3 or one 70 mg alendronate/5600 international units vitamin D 3 tablet once weekly. For most osteoporotic men, the appropriate dose is FOSAMAX PLUS D (70 mg alendronate/5600 international units vitamin D 3 ) once weekly. 2.3 Important Administration Instructions Instruct patients to do the following: Take FOSAMAX PLUS D at least one-half hour before the first food, beverage, or medication of the day with plain water only [see Patient Counseling Information (17) ] . Other beverages (including mineral water), food, and some medications are likely to reduce the absorption of alendronate [see Drug Interactions (7.1) ] . Waiting less than 30 minutes, or taking FOSAMAX PLUS D with food, beverages (other than plain water) or other medications will lessen the effect of alendronate by decreasing its absorption into the body. Take FOSAMAX PLUS D upon arising for the day. To facilitate delivery to the stomach and thus reduce the potential for esophageal irritation, a FOSAMAX PLUS D tablet should be swallowed with a full glass of water (6-8 ounces). Patients should not lie down for at least 30 minutes and until after their first food of the day. FOSAMAX PLUS D should not be taken at bedtime or before arising for the day. Failure to follow these instructions may increase the risk of esophageal adverse experiences [see Warnings and Precautions (5.1) and Patient Counseling Information (17) ] . 2.4 Recommendations for Calcium and Vitamin D Supplementation Instruct patients to take supplemental calcium if dietary intake is inadequate [see Warnings and Precautions (5.2) ] . Patients at increased risk for vitamin D insufficiency (e.g., over the age of 70 years, nursing home bound, or chronically ill) may need additional vitamin D supplementation. Patients with gastrointestinal malabsorption syndromes may require higher doses of vitamin D supplementation and measurement of 25-hydroxyvitamin D should be considered. The recommended intake of vitamin D is 400-800 international units daily. FOSAMAX PLUS D 70 mg/2800 international units and 70 mg/5600 international units are intended to provide seven days' worth of 400 and 800 international units daily vitamin D in a single, once-weekly dose, respectively. 2.5 Administration Instructions for Missed Doses If a once-weekly dose of FOSAMAX PLUS D is missed, instruct patients to take one tablet on the morning after they remember. They should not take two tablets on the same day but should return to taking one tablet once a week, as originally scheduled on their chosen day.

6 ADVERSE REACTIONS The following clinically significant adverse drug reactions are described elsewhere in the labeling: Upper Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.1) ] Mineral Metabolism [see Warnings and Precautions (5.2) ] Musculoskeletal Pain [see Warnings and Precautions (5.3) ] Osteonecrosis of the Jaw [see Warnings and Precautions (5.4) ] Atypical Fractures Including Femoral Fractures [see Warnings and Precautions (5.5) ] Renal Impairment [see Warnings and Precautions (5.6) ] Most common adverse reactions (greater than or equal to 3%) for alendronate are: abdominal pain, acid regurgitation, constipation, diarrhea, dyspepsia, musculoskeletal pain, nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Organon LLC, a subsidiary of Organon & Co., at 1-844-674-3200 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. FOSAMAX Treatment of Osteoporosis in Postmenopausal Women FOSAMAX Daily The safety of FOSAMAX in the treatment of postmenopausal osteoporosis was assessed in four clinical trials that enrolled 7453 women aged 44-84 years. Study 1 and Study 2 were identically designed, three-year, placebo-controlled, double-blind, multicenter studies (United States and Multinational; n=994); Study 3 was the three-year vertebral fracture cohort of the Fracture Intervention Trial [FIT] (n=2027); and Study 4 was the four-year clinical fracture cohort of FIT (n=4432). Overall, 3620 patients were exposed to placebo and 3432 patients exposed to FOSAMAX. Patients with pre-existing gastrointestinal disease and concomitant use of non-steroidal anti-inflammatory drugs were included in these clinical trials. In Study 1 and Study 2 all women received 500 mg elemental calcium as carbonate. In Study 3 and Study 4 all women with dietary calcium intake less than 1000 mg per day received 500 mg calcium and 250 international units Vitamin D per day. Among patients treated with alendronate 10 mg or placebo in Study 1 and Study 2, and all patients in Study 3 and Study 4, the incidence of all-cause mortality was 1.8% in the placebo group and 1.8% in the FOSAMAX group. The incidence of serious adverse event was 30.7% in the placebo group and 30.9% in the FOSAMAX group. The percentage of patients who discontinued the study due to any clinical adverse event was 9.5% in the placebo group and 8.9% in the FOSAMAX group. Adverse reactions from these studies considered by the investigators as possibly, probably, or definitely drug related in greater than or equal to 1% of patients treated with either FOSAMAX or placebo are presented in Table 1. Table 1: Osteoporosis Treatment Studies in Postmenopausal Women Adverse Reactions Considered Possibly, Probably, or Definitely Drug Related by the Investigators and Reported in Greater Than or Equal to 1% of Patients United States/Multinational Studies Fracture Intervention Trial FOSAMAX 10 mg/day for three years % (n=196) Placebo % (n=397) FOSAMAX 5 mg/day for 2 years and 10 mg/day for either 1 or 2 additional years % (n=3236) Placebo % (n=3223) Gastrointestinal abdominal pain nausea dyspepsia constipation diarrhea flatulence acid regurgitation esophageal ulcer vomiting dysphagia abdominal distention gastritis 6.6 3.6 3.6 3.1 3.1 2.6 2.0 1.5 1.0 1.0 1.0 0.5 4.8 4.0 3.5 1.8 1.8 0.5 4.3 0.0 1.5 0.0 0.8 1.3 1.5 1.1 1.1 0.0 0.6 0.2 1.1 0.1 0.2 0.1 0.0 0.6 1.5 1.5 1.2 0.2 0.3 0.3 0.9 0.1 0.3 0.1 0.0 0.7 Musculoskeletal musculoskeletal (bone, muscle or joint) pain muscle cramp 4.1 0.0 2.5 1.0 0.4 0.2 0.3 0.1 Nervous System/Psychiatric headache dizziness 2.6 0.0 1.5 1.0 0.2 0.0 0.2 0.1 Special Senses taste perversion 0.5 1.0 0.1 0.0 Rash and erythema have occurred. Gastrointestinal Adverse Reactions: One patient treated with FOSAMAX (10 mg/day), who had a history of peptic ulcer disease and gastrectomy and who was taking concomitant aspirin, developed an anastomotic ulcer with mild hemorrhage, which was considered drug related. Aspirin and FOSAMAX were discontinued and the patient recovered. In the Study 1 and Study 2 populations, 49-54% had a history of gastrointestinal disorders at baseline, and 54-89% used nonsteroidal anti-inflammatory drugs or aspirin at some time during the studies. [See Warnings and Precautions (5.1) .] Laboratory Test Findings: In double-blind, multicenter, controlled studies, asymptomatic, mild, and transient decreases in serum calcium and phosphate were observed in approximately 18% and 10%, respectively, of patients taking FOSAMAX versus approximately 12% and 3% of those taking placebo. However, the incidences of decreases in serum calcium to less than 8.0 mg/dL (2.0 mM) and serum phosphate to less than or equal to 2.0 mg/dL (0.65 mM) were similar in both treatment groups. FOSAMAX Once-Weekly The safety of FOSAMAX 70 mg once weekly for the treatment of postmenopausal osteoporosis was assessed in a one-year, double-blind, multicenter study comparing FOSAMAX 70 mg once weekly and FOSAMAX 10 mg daily. The overall safety and tolerability profiles of once weekly FOSAMAX 70 mg and FOSAMAX 10 mg daily were similar. The adverse reactions considered by the investigators as possibly, probably, or definitely drug related in greater than or equal to 1% of patients in either treatment group are presented in Table 2. Table 2: Osteoporosis Treatment Studies in Postmenopausal Women Adverse Reactions Considered Possibly, Probably, or Definitely Drug Related by the Investigators and Reported in Greater Than or Equal to 1% of Patients Once Weekly FOSAMAX 70 mg % (n=519) FOSAMAX 10 mg/day % (n=370) Gastrointestinal abdominal pain dyspepsia acid regurgitation nausea abdominal distention constipation flatulence gastritis gastric ulcer 3.7 2.7 1.9 1.9 1.0 0.8 0.4 0.2 0.0 3.0 2.2 2.4 2.4 1.4 1.6 1.6 1.1 1.1 Musculoskeletal musculoskeletal (bone, muscle, joint) pain muscle cramp 2.9 0.2 3.2 1.1 Concomitant Use With Estrogen/Hormone Replacement Therapy In two studies (of one and two years' duration) of postmenopausal osteoporotic women (total: n=853), the safety and tolerability profile of combined treatment with FOSAMAX 10 mg once daily and estrogen ± progestin (n=354) was consistent with those of the individual treatments. Osteoporosis in Men In two placebo-controlled, double-blind, multicenter studies in men (a two-year study of FOSAMAX 10 mg/day and a one-year study of once weekly FOSAMAX 70 mg) the rates of discontinuation of therapy due to any clinical adverse event were 2.7% for FOSAMAX 10 mg/day vs. 10.5% for placebo, and 6.4% for once weekly FOSAMAX 70 mg vs. 8.6% for placebo. The adverse reactions considered by the investigators as possibly, probably, or definitely drug related in greater than or equal to 2% of patients treated with either FOSAMAX or placebo are presented in Table 3. Table 3: Osteoporosis Studies in Men Adverse Reactions Considered Possibly, Probably, or Definitely Drug Related by the Investigators and Reported in Greater Than or Equal to 2% of Patients Two-year Study One-year Study FOSAMAX 10 mg/day % (n=146) Placebo % (n=95) Once Weekly FOSAMAX 70 mg % (n=109) Placebo % (n=58) Gastrointestinal acid regurgitation flatulence gastroesophageal reflux disease dyspepsia diarrhea abdominal pain nausea 4.1 4.1 0.7 3.4 1.4 2.1 2.1 3.2 1.1 3.2 0.0 1.1 1.1 0.0 0.0 0.0 2.8 2.8 2.8 0.9 0.0 0.0 0.0 0.0 1.7 0.0 3.4 0.0 FOSAMAX PLUS D In a fifteen-week double-blind, multinational study in osteoporotic postmenopausal women (n=682) and men (n=35), the safety profile of FOSAMAX PLUS D (70 mg/2800 international units) was similar to that of FOSAMAX once weekly 70 mg. In the 24-week double-blind extension study in women (n=619) and men (n=33), the safety profile of FOSAMAX PLUS D (70 mg/2800 international units) administered with an additional 2800 international units vitamin D 3 was similar to that of FOSAMAX PLUS D (70 mg/2800 international units). 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of FOSAMAX, FOSAMAX PLUS D, or bisphosphonate products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: hypersensitivity reactions including urticaria and angioedema. Transient symptoms of myalgia, malaise, asthenia and rarely, fever have been reported with alendronate, typically in association with initiation of treatment. Symptomatic hypocalcemia has occurred, generally in association with predisposing conditions. Peripheral edema. Gastrointestinal: esophagitis, esophageal erosions, esophageal ulcers, esophageal stricture or perforation, and oropharyngeal ulceration. Gastric or duodenal ulcers, some severe and with complications have also been reported [see Dosage and Administration (2.3) and Warnings and Precautions (5.1) ] . Localized osteonecrosis of the jaw, generally associated with tooth extraction and/or local infection with delayed healing, has been reported [see Warnings and Precautions (5.4) ] . Musculoskeletal: bone, joint, and/or muscle pain, occasionally severe, and incapacitating [see Warnings and Precautions (5.3) ] ; joint swelling; low-energy femoral shaft and subtrochanteric fractures, and atypical fractures of other bones [see Warnings and Precautions (5.5) ] . Nervous System: dizziness and vertigo. Pulmonary: acute asthma exacerbations. Skin: rash (occasionally with photosensitivity), pruritus, alopecia, severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Special Senses: uveitis, scleritis or episcleritis. Cholesteatoma of the external auditory canal (focal osteonecrosis).

12.3 Pharmacokinetics Absorption Alendronate Sodium Relative to an intravenous reference dose, the mean oral bioavailability of alendronate in women was 0.64% for doses ranging from 5 to 70 mg when administered after an overnight fast and two hours before a standardized breakfast. Oral bioavailability of the 10-mg tablet in men (0.59%) was similar to that in women when administered after an overnight fast and 2 hours before breakfast. In a study, the alendronate in the FOSAMAX PLUS D (70 mg/2800 international units) tablet and the FOSAMAX (alendronate sodium) 70-mg tablet were found to be equally bioavailable. In a separate study, the alendronate in the FOSAMAX PLUS D (70 mg/5600 international units) tablet was found to be equally bioavailable to the alendronate in the FOSAMAX (alendronate sodium) 70-mg tablet. A study examining the effect of timing of a meal on the bioavailability of alendronate was performed in 49 postmenopausal women. Bioavailability was decreased (by approximately 40%) when 10 mg alendronate was administered either 0.5 or 1 hour before a standardized breakfast, when compared to dosing 2 hours before eating. In studies of treatment and prevention of osteoporosis, alendronate was effective when administered at least 30 minutes before breakfast. Bioavailability was negligible whether alendronate was administered with or up to two hours after a standardized breakfast. Concomitant administration of alendronate with coffee or orange juice reduced bioavailability by approximately 60%. Cholecalciferol Following administration of FOSAMAX PLUS D (70 mg/2800 international units) after an overnight fast and two hours before a standard meal, the baseline adjusted mean area under the serum-concentration-time curve (AUC 0-120 hrs ) for vitamin D 3 was 120.7 ng-hr/mL. The baseline adjusted mean maximal serum concentration (C max ) of vitamin D 3 was 4.0 ng/mL, and the baseline adjusted mean time to maximal serum concentration (T max ) was 10.6 hrs. The bioavailability of the 2800 international units vitamin D 3 in FOSAMAX PLUS D is similar to 2800 international units vitamin D 3 administered alone. In a separate study, the baseline adjusted mean AUC 0-80 hrs and baseline adjusted mean C max for vitamin D 3 were 355.6 ng-hr/mL and 10.8 ng/mL, respectively. The baseline adjusted mean T max was 9.2 hrs. The bioavailability of the 5600 international units vitamin D 3 in the FOSAMAX PLUS D is similar to 5600 international units vitamin D 3 administered as two 2800 international units vitamin D 3 tablets. Distribution Alendronate Sodium Preclinical studies (in male rats) show that alendronate transiently distributes to soft tissues following 1 mg/kg intravenous administration but is then rapidly redistributed to bone or excreted in the urine. The mean steady-state volume of distribution, exclusive of bone, is at least 28 L in humans. Concentrations of drug in plasma following therapeutic oral doses are too low (less than 5 ng/mL) for analytical detection. Protein binding in human plasma is approximately 78%. Cholecalciferol Following absorption, vitamin D 3 enters the blood as part of chylomicrons. Vitamin D 3 is rapidly distributed mostly to the liver where it undergoes metabolism to 25-hydroxyvitamin D 3 , the major storage form. Lesser amounts are distributed to adipose tissue and stored as vitamin D 3 at these sites for later release into the circulation. Circulating vitamin D 3 is bound to vitamin D-binding protein. Metabolism Alendronate Sodium There is no evidence that alendronate is metabolized in animals or humans. Cholecalciferol Vitamin D 3 is rapidly metabolized by hydroxylation in the liver to 25-hydroxyvitamin D 3 , and subsequently metabolized in the kidney to 1,25-dihydroxyvitamin D 3 , which represents the biologically active form. Further hydroxylation occurs prior to elimination. A small percentage of vitamin D 3 undergoes glucuronidation prior to elimination. Excretion Alendronate Sodium Following a single intravenous dose of [ 14 C]alendronate, approximately 50% of the radioactivity was excreted in the urine within 72 hours and little or no radioactivity was recovered in the feces. Following a single 10-mg intravenous dose, the renal clearance of alendronate was 71 mL/min (64, 78; 90% confidence interval [CI]), and systemic clearance did not exceed 200 mL/min. Plasma concentrations fell by more than 95% within 6 hours following intravenous administration. The terminal half-life in humans is estimated to exceed 10 years, probably reflecting release of alendronate from the skeleton. Based on the above, it is estimated that after 10 years of oral treatment with FOSAMAX (10 mg daily) the amount of alendronate released daily from the skeleton is approximately 25% of that absorbed from the gastrointestinal tract. Cholecalciferol When radioactive vitamin D 3 was intravenously administered to healthy subjects, the mean urinary excretion of radioactivity after 48 hours was 2.4% of the administered dose, and the mean fecal excretion of radioactivity after 48 hours was 4.9% of the administered dose. In both cases, the excreted radioactivity was almost exclusively as metabolites of the parent. The mean half-life of baseline adjusted vitamin D 3 in the serum following an oral dose of FOSAMAX PLUS D is approximately 14 hours. Specific Populations Gender: Bioavailability and the fraction of an intravenous dose of alendronate excreted in urine were similar in men and women. Geriatric: Alendronate Sodium Bioavailability and disposition of alendronate (urinary excretion) were similar in elderly and younger patients. No dosage adjustment of alendronate is necessary. Cholecalciferol Dietary requirements of vitamin D 3 are increased in the elderly. Race: Pharmacokinetic differences due to race have not been studied. Renal Impairment: Alendronate Sodium Preclinical studies show that, in rats with kidney failure, increasing amounts of drug are present in plasma, kidney, spleen, and tibia. In healthy controls, drug that is not deposited in bone is rapidly excreted in the urine. No evidence of saturation of bone uptake was found after 3 weeks dosing with cumulative intravenous doses of 35 mg/kg in young male rats. Although no formal renal impairment pharmacokinetic study has been conducted in patients, it is likely that, as in animals, elimination of alendronate via the kidney will be reduced in patients with impaired renal function. Therefore, somewhat greater accumulation of alendronate in bone might be expected in patients with impaired renal function. No dosage adjustment is necessary for patients with creatinine clearance 35 to 60 mL/min. FOSAMAX PLUS D is not recommended for patients with creatinine clearance less than 35 mL/min due to lack of experience with alendronate in renal failure. Cholecalciferol Patients with renal insufficiency will have decreased ability to form the active 1,25-dihydroxyvitamin D 3 metabolite. Hepatic Impairment: Alendronate Sodium As there is evidence that alendronate is not metabolized or excreted in the bile, no studies were conducted in patients with hepatic impairment. No dosage adjustment is necessary. Cholecalciferol Vitamin D 3 may not be adequately absorbed in patients who have malabsorption due to inadequate bile production. Drug Interactions Alendronate Sodium Intravenous ranitidine was shown to double the bioavailability of oral alendronate. The clinical significance of this increased bioavailability and whether similar increases will occur in patients given oral H 2 -antagonists is unknown. In healthy subjects, oral prednisone (20 mg three times daily for five days) did not produce a clinically meaningful change in the oral bioavailability of alendronate (a mean increase ranging from 20 to 44%). Products containing calcium and other multivalent cations are likely to interfere with absorption of alendronate. Cholecalciferol Olestra, mineral oils, orlistat, and bile acid sequestrants (e.g., cholestyramine, colestipol) may impair the absorption of vitamin D. Anticonvulsants, cimetidine, and thiazides may increase the catabolism of vitamin D.